3-oxopyridazinylthiomethyl derivatives of ureidocephalosporins

ABSTRACT

Ureido cephalosporin derivatives of the formula ##STR1## wherein R is hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-lower alkyl, tri(lower alkyl)silyl, trihaloethyl, a salt forming ion, or the group ##STR2## R 1  is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl, cycloalkadienyl, phenyl, phenyl-lower alkyl, substituted phenyl or phenyl-lower alkyl, or certain heterocyclic groups; R 2  is hydrogen or lower alkyl; R 3  is hydrogen or methoxy; R 4  is hydrogen, halogen, lower alkyl, or lower alkoxy; R 5  is hydrogen or lower alkyl; R 6  is lower alkyl, phenyl, or phenyl-lower alkyl; are disclosed. These compounds are useful as antibacterial agents.

This is a division, of application Ser. No. 611,041, filed Sept. 8,1975, now U.S. Pat. No. 3,996,218.

BACKGROUND OF THE INVENTION

Cephalosporins having a ureido acyl side chain are disclosed in U.S.Pat. Nos. 3,673,183; 3,833,568; and 3,708,479. Cephalosporins having an(oxopyridazinyl)thiomethyl group in the 3-position are disclosed inBritish Pat. No. 1,363,333. Cephalosporins having a methoxy group in the7α-position are disclosed in various U.S. patents including U.S. Pat.Nos. 3,775,410; 3,780,031; 3,780,033; 3,780,034; 3,780,037, etc.

SUMMARY OF THE INVENTION

This invention relates to new oxopyridazinylthiomethyl derivatives ofureido-7α-methoxy or desmethoxy cephalosporins of the formula ##STR3##

R represents hydrogen, lower alkyl, phenyl-lower alkyl, diphenyl-loweralkyl, tri(lower alkyl)silyl, trihaloethyl, a salt forming ion, or thegroup ##STR4## R₁ represents hydrogen, lower alkyl, cycloalkyl,cycloalkenyl, cycloalkadienyl, phenyl, phenyl-lower alkyl, substitutedphenyl or phenyl-lower alkyl, or certain heterocyclics; R₂ representshydrogen or lower alkyl; R₃ represents hydrogen or methoxy; R₄represents hydrogen, halogen, lower alkyl of 1-4 carbons, or loweralkoxy of 1-4 carbons; R₅ represents hydrogen or lower alkyl; and R₆represents lower alkyl, phenyl or phenyl-lower alkyl.

DETAILED DESCRIPTION OF THE INVENTION

The various groups represented by the symbols have the meaning definedbelow and these definitions are retained throughout this specification.

The lower alkyl groups referred to throughout this specification includestraight or branched chain hydrocarbon groups containing 1 to 8 carbonatoms, preferably 1 to 4 carbons. Examples of the type of groupscontemplated are methyl, ethyl, propyl, isopropyl, butyl, t-butyl, etc.The lower alkoxy groups include such lower alkyl groups attached to anoxygen, e.g., methoxy, ethoxy, propoxy, etc. The phenyl-lower alkyl anddiphenyl-lower alkyl groups include such lower alkyl groups attached toa phenyl, preferably benzyl, phenethyl, and diphenylmethyl.

Cycloalkyl refers to groups having 3 to 7 carbons in the ring, i.e.cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Theterms cycloalkenyl and cycloalkadienyl also represent rings having 3 to7 carbons with one or two double bonds, i.e. cyclobutenyl,cyclopentenyl, cyclohexenyl, cyclopentadienyl, cyclohexadienyl, etc. Thedouble bond or bonds may be located at various positions, i.e.1,4-cyclohexadienyl, etc.

The substituted phenyl and substituted phenyl-lower alkyl groups includeone to three (preferably only one) simple substituents selected fromhalogen (preferably chlorine or bromine), lower alkyl, lower alkoxy, andhydroxy, e.g. 2-, 3-, or 4-chlorophenyl, 2-, 3- or 4-bromophenyl,3,5-dichlorophenyl, 2-methylphenyl, 4-ethoxyphenyl,3,4,5-trimethoxyphenyl, 2-, 3- or 4-chlorobenzyl, 2-, 3-, or4-methylphenethyl, etc.

The salt forming ions represented by R may be metal ions, e.g.,aluminum, alkali metal ions such as sodium or potassium, alkaline earthmetal ions such as calcium or magnesium, or an amine salt ion, of whicha number are known for this purpose, for example, phenyl-loweralkylamines such as dibenzylamine, N,N-dibenzylethylenediamine, loweralkylamines such as methylamine, triethylamine, and N-loweralkylpiperidines such as N-ethylpiperidine.

The halogens are the four common halogens, of which chlorine and bromineare preferred. In the case of the trihaloethyl group represented byR,2,2,2-trichloroethyl is preferred.

Trimethylsilyl is the preferred tri(lower alkyl)silyl group.

The heterocyclics represented by R₁ are thienyl, furyl, pyrryl, pyridyl,thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, andtetrazolyl. They are attached at any available carbon atom as forexample 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrryl, 2-, 3- or4-pyridyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-(1,2,4-thiadiazolyl), etc.Also included within the meaning of R₁ are such heterocyclics having ahalogen (preferably Cl or Br) or a lower alkyl of 1-4 carbons(preferably methyl or ethyl) substituent, i.e. 5-(1-methyltetrazolyl),2-(5-chlorothienyl), 2-(4-chloropyrryl), etc.

The structural formula for the pyridazine refers to the 1-oxide and tothe 2-oxide.

The broken lines (.tbd.) between the cephalosporin nucleus and R₃indicate that this substituent is in the α-configuration.

Preferred embodiments of this invention are as follows:

R₁ is phenyl, benzyl, phenethyl, substituted phenyl, benzyl, orphenethyl, cycloalkyl, cycloalkenyl and cycloalkadienyl of 5 to 7carbons, thienyl, furyl, pyrryl, or pyridyl.

R₂ is hydrogen or lower alkyl of 1 to 4 carbons.

R is hydrogen, lower alkyl of 1 to 4 carbons, benzyl, phenethyl,diphenylmethyl, trimethylsilyl, 2,2,2-trichloroethyl, aluminum, alkalineearth metal, alkali metal, or ##STR5## wherein R₆ is lower alkyl of 1 to4 carbons, phenyl, benzyl or phenethyl.

R₄ is hydrogen.

The most preferred embodiments are:

R₁ is phenyl, substituted phenyl, 1,4-cyclohexadien-1-yl, 2-thienyl,3-thienyl, or 3-pyridyl.

R₂ is hydrogen or methyl.

R is hydrogen, t-butyl, diphenylmethyl, or potassium.

Compounds of formula I are obtained by reacting an α-ureido compound ofthe formula ##STR6## with a 3-heterothio-7-amino substitutedcephalosporin of the formula ##STR7## wherein R is preferablydiphenylmethyl or t-butyl or other ester protecting groups.

This reaction is carried out by converting the α-ureido compound offormula II to a mixed carbonic or other anhydride by treating a solutionof the α-ureido compound in an organic solvent containing a tri(loweralkyl)amine with an anhydride forming agent, i.e. a lower alkylchloroformate, an aryl chloroformate, or an acyl halide, at reducedtemperatures of from about 0° C to about -20° C.

Alternatively, the α-ureido compound of formula II can be converted toan activated ester by reacting with a carboxyl group activating agentsuch as dicyclohexylcarbodiimide or bisimidazole carbonyl. In some casesthe carboxyl group may be activated by conversion to an acid halide,e.g. the chloride, or to an azide.

The methods of preparing the α-ureido compounds of formula II are knownto those skilled in the art and a number of such methods are discussedin U.S. Pat. Nos. 3,673,183 and 3,833,568 referred to above.

The compounds of formula I can also be prepared by acylating thecompound of formula III with an acid chloride of formula ##STR8## or anα-(substituted)amino acid of the formula ##STR9## wherein Y is aprotecting group such as ##STR10## to yield after removal of theprotecting group the intermediate of formula ##STR11##

The intermediate of formula VI is converted to the final products offormula I by treatment with an isocyanate of the formula

    R.sub.2 --N═C═O                                    (VII)

or when R₂ is hydrogen an alkali or alkaline earth cyanate such aspotassium cyanate in solution at a pH of from about 7 to about 8.

The final products of formula I wherein R₃ and R are hydrogen can alsobe prepared by reacting the compound of formula II with 7-ACA to yieldthe compound of formula VIII ##STR12## followed by treatment with thecompound of the formula ##STR13## or a salt thereof, preferably analkali metal salt like the potassium or sodium salt. This reaction iseffected by bringing together the reactants in an aqueous solvent,preferably at a slightly alkaline pH with heating and under an inertatmosphere like nitrogen.

The starting material of formula IX is prepared as described in BritishPat. No. 1,363,333.

Similarly, the final products of formula I can be prepared by reactingthe compounds of formula IV or V with an ester of 7-ACA or7α-methoxy-7ACA preferably in the presence of dicyclohexylcarbodiimidefollowed by treatment with an acid (HX), preferably trifluoroacetic acidin the presence of anisole, to yield the salt of formula ##STR14##

The salt of formula X is treated with the isocyanate of formula VII (orthe alkali or alkaline earth cyanate where R₂ is hydrogen) followed bytreatment with the compound of formula IX as described above to yieldthe final product of formula I.

The compounds of formula I wherein R is lower alkyl, phenyl-lower alkyl,substituted phenyl-lower alkyl, diphenyl-lower alkyl, or theacyloxymethyl group ##STR15## may be obtained by reacting the3-heterothio-7-amino substituted cephalosporin of formula III or the7-ACA or the 7α-methoxy-7ACA either before or after the acylation of the7-amino substituent with one or two moles of a compound of the formula

    halo-R                                                     (XI)

or

R═n⁺ ═n⁻ (xii)

wherein halo is preferably chlorine or bromine in an inert solvent suchas dimethylformamide, acetone, dioxane, benzene, or the like at aboutambient temperature or below.

Similarly, the compounds of formula I wherein R is tri(lower alkyl)silylare obtained by introducing such groups onto the 3-heterothiocephalosporanic acid moiety either before or after the acylationreaction.

The carboxylate salts of the compound of formula I are formed byreacting the carboxyl group of the cephalosporanic acid moiety, i.e. Ris hydrogen, with any of the salt forming ions described above.

It will be appreciated that the compounds of formula I are opticallyactive due to the presence of an asymmetric carbon atom in the7-position side chain. By selection of the appropriate starting materialit is possible to obtain the compounds of formula I as a mixture ofoptically active isomers or isolated as a single isomer. The variousisomers as well as their mixtures are within the scope of thisinvention. Where possible, it is generally preferred to obtain theD-isomer since that is the one which exhibits greater biologicalactivity.

Illustrative process details are provided in the examples for thevarious reactions.

The compounds of formula I have a broad spectrum of antibacterialactivity against both gram positive and gram negative organisms such asStaphylococcus aureus, Salmonella schottmuelleri, Pseudomonasaeruginosa, Proteus vulgaris, Escherichia coli and Streptococcuspyogenes. They may be used as antibacterial agents in a prophylacticmanner, e.g., in cleaning or as surface disinfecting compositions, orotherwise to combat infections due to organisms such as those namedabove, and in general may be utilized in a manner similar to cephalothinand other cehalosporins. For example, a compound of formula I or aphysiologically acceptable salt thereof may be used in various animalspecies in an amount of about 1 to 100 mg./kg., daily, orally orparenterally, in single or two to four divided doses to treat infectionsof bacterial origin, e.g., 5.0 mg./kg. in mice.

Up to about 600 mg. of a compound of formula I or a physiologicallyacceptable salt thereof may be incorporated in an oral dosage form suchas tablets, capsules or elixirs or in an injectable form in a sterileaqueous vehicle prepared according to conventional pharmaceuticalpractice.

They may also be used in cleaning or disinfecting compositions, e.g.,for cleaning barns or dairy equipment, at a concentration of about 0.2to 1% by weight of such compounds admixed with, suspended or dissolvedin conventional inert dry or aqueous carriers for application by washingor spraying.

They are also useful as nutritional supplements in animal feeds.

The following examples are illustrative of the invention. Alltemperatures are on the centrigrade scale.

EXAMPLE 1 7β-[[[(Aminocarbonyl)amino)(DL-2-thienyl)acetyl]amino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(a) DL-α-ureido-2-thiopheneacetic acid

15.8 g. (0.1 mol.) of DL-2-thienylglycine are heated together with 8.2g. (0.1 mol.) of potassium cyanate in 100 ml. of water. After 30minutes, the mixture is cooled and acidified with dilute hydrochlorideacid. The precipitated product, DL-α-ureido-2-thiopheneacetic acid, isfiltered, washed with ice water and a small amount of ethanol.Recrystallization from methanol yields 17 g. of white crystals, ofDL-α-ureido-2-thiopheneacetic acid; m.p. 183°-185°.

(b)3-[(Acetyloxy)methyl]-7β-[[[(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

9.2 g. (50 mmol.) of DL-α-ureido-2-thiopheneacetic acid from part (a)are dissolved in 40 ml. of absolute dimethylformamide. 10.3 g. (50mmol.) of dicyclohexylcarbodiimide dissolved in 10 ml. of methylenechloride are added dropwise at 0°. After stirring for 1/2 hour, asolution of 13.5 g. (50 mmol.) of 7-aminocephalosporanic acid and 10 g.(100 mmol.) of triethylamine is added. This mixture is stirred for 24hours at 5°. After filtering, the filtrate is concentrated under vacuum,the oily residue is taken up in water, filtered and after treating withactivated carbon at 5° it is layered over with ethyl acetate andacidified with 2N hydrochloric acid. The ethyl acetate solution iswashed with water, dried and concentrated. 8.1 g. of a viscid residueare obtained. The product,3-[(acetyloxy)methyl]-7β-[[[(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-carboxylicacid, is recrystallized twice from isopropanol; yield 2.1 g. Theintermediate of part (b) can also be obtained by the followingsynthesis:

(c) DL-[[[(1,1-Dimethylethoxy)carbonyl]amino]thien-2-yl]acetic acid

3.8 g. (25 mmol.) of DL-2-thienylglycine and 2 g. (50 mmol.) ofmagnesium oxide in 50 ml. of water/dioxane (1:1) are stirred for 1 hourat room temperature. 4.25 g. (28 mmol.) of t-butyloxycarbonylazidedissolved in 15 ml. of dioxane are added dropwise and the reactionmixture is stirred for 24 hours at 50°. After filtering, the filtrate isconcentrated under vacuum, the oily residue is treated with ethylacetate and then taken up with water. This is then acidified with citricacid while cooling with ice and the aqueous acid solution is extractedwith ethyl acetate. The solvent is drawn off from the ethyl acetatesolution to obtain 4 g. of white product,DL-[[[(1,1-dimethylethoxy)carbonyl]amino]thien-2-yl]acetic acid; m.p.70°-72°.

(d)3-[(Acetyloxy)methyl]-7β-[[[[(1,1-dimethylethoxy)carbonyl]-amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester

5.4 g. (20 mmol.) ofDL-[[[(1,1-dimethylethoxy)carbonyl]amino]thien-2-yl]acetic acid frompart (c) are dissolved in 50 ml. of tetrahydrofuran and 4.05 g. (20mmol.) of dicyclohexylcarbodiimide are added at 0°. After stirring for30 minutes, 8.8 g. (20 mmol.) of 7-aminocephalosporanic acid,diphenylmethyl ester are added dropwise. After 24 hours, theprecipitated dicyclohexylurea is filtered off. After drawing off thesolvent and recrystallizing the beige residue from methylenechloride/potassium ether 10.5 g. of the product,3-[(acetyloxy)methyl-7β-[[[[(1,1-dimethylethoxy)carbonyl]amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, diphenylmethyl ester, are obtained as a light beige powder; m.p78° (dec.).

(e)3-[(Acetyloxy)methyl]-7β-[[[(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0.]oct-2-ene-2-carboxylicacid

5 g. of3-[(acetyloxy)methyl]-7β-[[[[(1,1-dimethylethoxy)carbonyl]amino[(DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester from part (a)are stirred for 15 minutes in a mixture of 20 ml. of trifluoroaceticacid and 3 ml. of anisole at 5°. After evaporating the trifluoroaceticacid under vacuum and washing the residue with ether, 2.3 g. of3-[(acetyloxy)methyl]-7β-[[(2-amino-DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetic acid salt areobtained. This product is dissolved in water and the solution isadjusted to pH 8 with sodium hydroxide. It is then quickly heated to 80°and 0.4 g. of potassium cyanate dissolved in 2 ml. of water are added.After stirring for 1 minute, the reaction mixture is quickly cooled,layered over with ethyl acetate and acidified to pH 3.5 with 2Nhydrochloric acid. This is extracted with 5 × 100 ml. of ethyl acetate.The combined ethyl acetate extracts are dried, concentrated to about 1/3the volume, treated with activated carbon and the product,3-[(acetyloxy)methyl]-7β-[[[(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, is precipitated with petroleum ether. Theproduct is crystallized from isopropanol as light being crystals; m.p.145° (dec.).

(f) 7β-[ [ [ (Aminocarbonyl)amino](DL-2-thienyl)acetyl]amino] -3-[ [(1oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

The 3-[(acetyloxy)methyl]-7β-[ [ [(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo [4.2.0]- oct-2-ene-2-carboxylic acid frompart (b) or (e) is dissolved in a mixture of acetone/water (1:1) withthe aid of 5N sodium hydroxide. 1-oxopyridazine3-thiol, sodium salt isadded under nitrogen and the solution is heated for several hours at 60°. The solution is diluted with 150 ml. of water and acidified to pH 5with 2N hydrochloric acid while cooling. A precipitate forms which isfiltered under suction to yield 7β-[ [ [ (aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[ [ (1-oxopyridazin- 3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

EXAMPLE 2 7β-[ [ [ (Aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[ (1-oxopyridazin-3-yl)thio] methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 -carboxylic acid, potassiumsalt

An equimolar solution of the final product from example 1 and potassiumbicarbonate is freeze-dried to yield the titled compound as a powder.

EXAMPLE 3 7β-[ [ [ (Aminocarbonyl)amino](DL-3-thienyl)acetyl]amino]-3-[[(1-oxapyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(a) DL-α-Bromo-3-thiopheneacetic acid

3-thienylbromide is treated with butyl lithium and chloral to obtain3-[(1-hydroxy-2 -trichloro)ethyl]thiophene which is then treated withsodium methoxide to obtain α-methoxy-3-thienylacetic acid [Gronowitz etal., Ark. Chemi., 17, 561 (1961)].

150 ml. of 30% hydrogen bromide in acetic acid is added to a solution of16 g. (100 mmol.) of (α-methoxy-3-thienyl)acetic acid in 50 ml. ofglacial acetic acid. The mixture is left to stand at room temperaturefor 24 hours and then poured into ice water. The solution is extractedthree times with 60 ml. of ether. The ether phase is washed with water,dried over magnesium sulfate and evaporated. The residue, 18 g. of crudeDL-α-bromo-3-thiopheneacetic acid are recrystallized from cyclohexane;yield 14 g.; m.p. 80°-82° .

(b) DL-α-Azido-3-thiopheneacetic acid

4 g. (62 mmol.) of sodium azide and 3.5 g. (33 mmol.) of sodiumcarbonate are added to a solution to 12 g. (54 mmol.) of DL-α-bromo-3-thiopheneacetic acid in 75 ml. of acetone (96%). The mixture isstirred at room temperature for 12 hours in darkness and after this timethe solvent is evaporated and the residue is dissolved in 75 ml. ofwater. 50 ml. of ether is added, the water phase is acidified with 2Nsulfuric acid and extracted quickly twice more with 50 ml. of ether.After washing with water and drying over sodium sulfate, the combinedether phases are evaporated. Crystallization of the residue fromcyclohexane yields 7.4 g. of white crystalline DL-α-azido-3-thiopheneacetic acid; m.p. 58°-59° .

(c) DL-α-Amino-3-thiopheneacetic acid

0.3 g. of palladium/barium sulfate catalyst are added to a solution of 6g. of DL-α-azido-3-thiopheneacetic acid in 40 ml. of ethanol and 40 ml.of 0.5N hydrochloric acid. Hydrogenation takes place at about 60 psig.after 2 hours. After filtration, the volume is concentrated to about 30ml. When the pH is brought to 6.5 with ammonia, the amino acid separatesas a white powder. After washing with ethanol/water and drying, 3.5 g.of the product, DL-α-amino-3-thiopheneacetic acid, are obtained; m.p.283°-285° .

(d) DL-α-[ [ [(4-Methoxyphenyl)methoxy]carbonyl]amino]-3-thiopheneacetic acid

1.9 g. (12.5 mmol.) of DL-α-amino-3-thiopheneacetic acid and 1 g. ofmagnesium oxide are stirred in 25 ml. of water and 25 ml. of dioxane.After stirring for 1 hour, 3.0 g. (15 mmol.) of[(p-methoxybenzyl)oxy]carbonylazide are added. Stirring is continued for24 hours. The mixture is filtered and extracted with 20 ml. of ether. 50ml. of ethyl acetate and 20 g. of Dowex 50 (H⁺ form) are added to thefiltrate and the mixture is stirred well for 2 hours. The ethyl acetatephase is separated, washed with 50 ml. of water, dried over sodiumsulfate and evaporated. The oily residue crystallizes after the additionof pentane to yield 3.4 g. of white crystalline DL-α- [ [ [(4-methoxyphenyl)methoxy]carbonyl]amino]-3-thiopheneacetic acid; m.p.118° (dec.).

(e)3-[ (Acetyloxy)methyl]-7β-[ [ [ [ [(4-methoxyphenyl)methoxy]carbonyl]amino](DL-3-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid

5 g. of the product from part (d), 1.5 g. of triethylamine and 1.8 g. ofchloroformic acid ethyl ester in 50 ml. of tetrahydrofuran are convertedto the mixed anhydride. The mixed anhydride is reacted with a solutionof 4 g. of 7-aminocephalosporanic acid and 2.5 g. of triethylamine inmethylene chloride for 12 hours. The solvent is then removed from thesolution and the partially solid residue is dissolved with water and asmall amount of sodium carbonate and extracted with 50 ml. of ethylacetate. The aqueous phase is cooled, acidified to pH 2.5 with 2Nhydrochloric acid and extracted with ethyl acetate. The organic phase istreated with activated carbon and concentrated to obtain 3.7 g. of lightbeige product, 3-[(acetyloxy)methyl]-7β-[ [ [ [ [(4-methoxyphenyl)methoxy] carbonyl]amino] (DL-3-thienyl)acetyl] amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; m.p. 113°(dec.), which is recrystallized from methylene chloride/petroleum ether.

(f) 3-[(Acetyloxy)methyl]-7β-[ [ [ (aminocarbonyl)amino](DL-3-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid

The product from part (e) is stirred with 15 ml. of trifluoroacetic acidand then reacted with potassium cyanate as described in example 1(e) toyield the titled compound.

(g) 7β-[ [ [ (Aminocarbonyl)amino] (DL-3-thienyl)acetyl] amino] -3-[ [(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

The 3-[(acetyloxy)methyl]-7β-[ [ [(aminocarbonyl)amino]-(DL-3-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid frompart (f) is treated with 1- oxopyridazine-3-thiol according to theprocedure of example 1 (f) to yield the titled compound.

EXAMPLE 4 7β-[ [ [ (Aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-3-[ [(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(a) D-α-[ [ [ (4-Methoxyphenyl)methoxy] carbonyl] amino]-2-thiophene-acetic acid

15.7 g. of D-(2-thienyl)glycine (m.p. 218°-219°, produced from theracemate with D-camphor-10 -sulfonic acid) and 8 g. of magnesium oxideare suspended in 200 ml. of water. To this suspension is added asolution of 22.8 g. of (p-methoxyphenyl)methoxycarbonylazide in 200 ml.of dioxane and this mixture is stirred for 3 days at room temperature.The mixture is filtered, the filtrate is extracted once with ether, theaqueous phase is layered over with ethyl acetate, cooled to about 10°and acidified to pH 2 with dilute hydrochloric acid. The aqueous phaseis once more extracted with ethyl acetate, the combined extracts arewashed once with water, dried with magnesium sulfate and concentrated.The residue crystallizes upon trituration with petroleum ether. Thecrude product, D-α -[ [ [ (4-methoxyphenyl)methoxy] carbonyl] amino]-2-thiopheneacetic acid, is recrystallized from ethyl acetate/petroleumether, yield 25.2 g., m.p. 65°-67° .

(b) 3-[Acetyloxy)methyl] -7β-[ [ [ [ [(4-methoxyphenyl)methoxy]-carbonyl] amino] (D-2-thienyl)acetyl] amino]-7α -methoxy-8-oxo-5-thia-1-azabicyclo-[4.2.0] oct-2-ene-2-carboxylicacid, diphenylmethyl ester

3.2 g. (0.01 mol.) of the product from part (a) is brought into solutionin 40 ml. of methylene chloride with 1.1 ml. of N-methylmorpholine. Thesolution is cooled to -15° , 1.39 ml. of isobutylchloroformate areadded, and the mixture is stirred for 10 minutes. To this is added asolution of 4.7 g. (0.01 mol.) of 7β-amino-7α-methoxy cephalosporanicacid diphenylmethyl ester and 3.1 ml. of triethylamine in 40 ml. ofmethylene chloride. The mixture is stirred for 1 hour at -5° and 1 hourat 5°. This mixture is then evaporated to dryness in a rotary evaporatorand the solid residue is triturated with ether and filtered undersuction to yield the titled compound.

(c) 3-[(Acetyloxy)methyl]-7β -[ [(α-amino-D-2-thienyl)acetyl]amino]-7α-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

2.0 g. of the product from part (b) are added at -5° to a mixture of 10ml. of trifluoroacetic acid and 4 ml. of anisole. The mixture is stirredfor 15 minutes and is then concentrated in a rotary evaporator. Theresidue is treated with ether and filtered under suction. The crude3-[(acetyloxy)-methyl]-7β-[ [ (2-amino-D-2-thienyl)acetyl] amino] -7α-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid,trifluoroacetic acid salt is dissolved in 50 ml. of water and 20 ml. ofa solution of the acetate form of the ion exchange resin Amberlite LA 1in isobutylmethylketone are added. The mixture is stirred for 2 hours atroom temperature. The layers are separated, the aqueous phase is washedseveral times with ether and freeze-dried to yield3-[(acetyloxy)methyl]-7β -[ [ (α-amino-D-2-thienyl)acetyl] amino]-7α-methoxy8-oxo-5-thia-1-azabicyclo[ 4.2.0] oct-2-ene-2-carboxylicacid.

(d) 3[(Acetyloxy)methyl]-7β-[[[(aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

A mixture of 1 g. of the product from part (c) and 0.194 g. of potassiumcyanate in 7.5 ml. of water are quickly heated in a preheated bath at80°. The mixture is then immediately cooled to room temperature andpermitted to stand overnight. The reaction mixture is concentrated toabout 4 ml. and the pH is adjusted to 1.5 with 2N hydrochloric acid. Theprecipitate is filtered under suction to obtain3-[(acetyloxy)methyl]-7β-[[[(aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-carboxylic acid.

(e) 7β-[[[(Aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

0.01 moles of the product are part (d) and 0.011 moles of1-oxopyridazine-3-thiol are heated in an aqueous acetone solutionaccording to the procedure of example 1(f) to yield7β-[[[(aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

EXAMPLES 5-11

Following the procedure of example 1 but substituting for the1-oxopyridazine-3-thiol one of the following:

2-oxopyridazine-3-thiol

4-methyl-1-oxopyridazine-3-thiol

6-ethoxy-1-oxopyridazine-3-thiol

5-t-butyl-2-oxopyridazine-3-thiol

6-chloro-1-oxopyridazine-3-thiol

4-bromo-2-oxopyridazine-3-thiol

6-methoxy-2-oxopyridazine-3-thiol one obtains:

7β-[[[(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(2-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

7β-[[[(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3[[(4-methyl-1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

7β-[[[(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(6-ethoxy-1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

7β-[[[(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(5-t-butyl-2-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

7β-[[[(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(6-chloro-1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

7β-[[[(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(4-bromo-2-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, and

7β-[[[(aminocarbonyl)amino](DL-2-thienyl)acetyl]amino]3-[[(6-methoxy-2-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, respectively.

EXAMPLES 12-18

Following the procedure of example 4 but substituting for the1-oxopyridazine-3-thiol the pyridazines of examples 5-11 one obtains thefollowing compounds:

7β-[[[(aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7αmethoxy-3-[[(2-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

7β-[[[(aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7αmethoxy-3-[[(4-methyl-1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

7β-[[[(aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7αmethoxy-3-[[(6-ethoxy-1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

7β-[[[(aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7αmethoxy-3-[[(5-t-butyl-2-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

7β-[[[(aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7αmethoxy-3-[[(6-chloro-1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid,

7β-[[[(aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7αmethoxy-3-[[(4-bromo-2-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, and

7β-[[[(aminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7αmethoxy-3-[[(6-methoxy-2-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, respectively.

EXAMPLES 19-72

Following the procedure of either example 1 or 4 but employing theα-amino acid shown in Col. I one obtains the compound shown in Col. II(procedure of example I) or Col. III (procedure of example 4).

    ______________________________________                                        Col. I                                                                         ##STR16##                                                                    Col. II                                                                        ##STR17##                                                                    Col. III                                                                       ##STR18##                                                                    Ex.        R.sub.1                                                            ______________________________________                                        19          H                                                                 20         CH.sub.3                                                           21         C.sub.2 H.sub.5                                                    22         t-C.sub.4 H.sub.9                                                  23         n-C.sub.5 H.sub.11                                                 24                                                                                        ##STR19##                                                         25                                                                                        ##STR20##                                                         26                                                                                        ##STR21##                                                         27                                                                                        ##STR22##                                                         28                                                                                        ##STR23##                                                         29                                                                                        ##STR24##                                                         30                                                                                        ##STR25##                                                         31                                                                                        ##STR26##                                                         32                                                                                        ##STR27##                                                         33                                                                                        ##STR28##                                                         34                                                                                        ##STR29##                                                         35                                                                                        ##STR30##                                                         36                                                                                        ##STR31##                                                         37                                                                                        ##STR32##                                                         38                                                                                        ##STR33##                                                         39                                                                                        ##STR34##                                                         40                                                                                        ##STR35##                                                         41                                                                                        ##STR36##                                                         42                                                                                        ##STR37##                                                         43                                                                                        ##STR38##                                                         44                                                                                        ##STR39##                                                         45                                                                                        ##STR40##                                                         46                                                                                        ##STR41##                                                         47                                                                                        ##STR42##                                                         48                                                                                        ##STR43##                                                         49                                                                                        ##STR44##                                                         50                                                                                        ##STR45##                                                         51                                                                                        ##STR46##                                                         52                                                                                        ##STR47##                                                         53                                                                                        ##STR48##                                                         54                                                                                        ##STR49##                                                         55                                                                                        ##STR50##                                                         56                                                                                        ##STR51##                                                         57                                                                                        ##STR52##                                                         58                                                                                        ##STR53##                                                         59                                                                                        ##STR54##                                                         60                                                                                        ##STR55##                                                         61                                                                                        ##STR56##                                                         62                                                                                        ##STR57##                                                         63                                                                                        ##STR58##                                                         64                                                                                        ##STR59##                                                         65                                                                                        ##STR60##                                                         66                                                                                        ##STR61##                                                         67                                                                                        ##STR62##                                                         68                                                                                        ##STR63##                                                         69                                                                                        ##STR64##                                                         70                                                                                        ##STR65##                                                         71                                                                                        ##STR66##                                                         72                                                                                        ##STR67##                                                         ______________________________________                                    

EXAMPLE 73 7β-[[[(Methylaminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(a) 3-[(Acetyloxy)methyl]-7β-[[[(methylaminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

1.5 g. of3-[(acetyloxy)methyl]-7β-[[(2-amino-DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, trifluoroacetic acid salt from example 1(e) and 1.01 ml. oftriethylamine are dissolved at 0°-5° in 20 ml. of anhydrous methylenechloride. To the clear solution is added 2.49 g. of a 10% solution ofmethylisocyanate in methylene chloride. This mixture is stirred for 2hours at 0°-5° and then concentrated. The residue is taken up in alittle water, shaken with ether, filtered and acidified with 2Nhydrochloric acid to yield3-[(acetyloxy)methyl]-7β-[[[(methylaminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

(b) 7β-[[[(Methylaminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

0.01 mol. of the product from part (a) and 0.011 mol. of1-oxopyridazine-3-thiol are reacted according to the procedure ofexample 1(f) to yield 7β-[[[(methylaminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0.]oct-2-ene-2-carboxylic acid.

EXAMPLES 74-80

Following the procedure of example 73 but substituting for themethylisocyanate one of the following:

ethylisocyanate

n-propylisocyanate

i-propylisocyanate

n-butylisocyanate

i-butylisocyanate

t-butylisocyanate

n-pentylisocyanate

one obtains:

7β-[[[(ethylaminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid;

7β-[[[(n-propylaminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(I-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid;

7β-[[[(i-propylaminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;

7β-[[[(n-butylaminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid;

7β-[[[(i-butylaminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid;

7β-[[[(t-butylaminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid; and

7β-[[[(n-pentylaminocarbonyl)amino](DL-2-thienyl)acetyl]amino]-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid; respectively.

Similarly, by employing the methylisocyanate from example 73 or thealkylisocyanates of examples 74-80 in the procedure of examples 3, 5 to11, and 19 to 72, other compounds within the scope of this invention areobtained.

EXAMPLE 81 7β-[[[(Methylaminocarbonyl)amino] (D-2-thienyl)acetyl]amino]-7α-methoxy-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

(a) 3-[(Acetyloxy)methyl]-7β-[[[(methylaminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

1.5 g. of3-[(acetyloxy)methyl]-7β-[[(2-amino-D-2-thienyl)acetyl]amino]7α-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid, trifluoroacetic acid salt from example 4(c) and 1.01 ml. oftriethylamine are dissolved at 0°-5° in 20 ml. of anhydrous methylenechloride. To the clear solution is added 2.49 g. of a 10% solution ofmethylisocyanate in methylane chloride. This mixture is stirred for 2hours at 0°-5° and then concentrated. The residue is taken up in alittle water, shaken with ether, filtered and acidified with 2Nhydrochloric acid to yield3-[(acetyloxy)methyl]-7β-[[[(methylaminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

(b) 7β-[[[(Methylaminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid

0.01 mol. of the product from part (a) and 0.011 mol. of1-oxopyridazine-3-thiol are reacted according to the procedure ofexample 1(f) to yield 7β-[[[(methylaminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid.

EXAMPLES 82-88

Following the procedure of examples 81 but substituting for themethylisocyanate one of the following:

ethylisocyanate

n-propylisocyanate

i-propylisocyanate

n-butylisocyanate

i-butylisocyanate

t-butylisocyanate

n-pentylisocyanate

one obtains:

7β-[[[(ethylaminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid;

7β-[[[(n-propylaminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid;

7β-[[[(i-propylaminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid;

7β-[[[(n-butylaminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid;

7β-[[[(i-butylaminocarbonyl)amino](D-2-theinyl)acetyl]amino]-7α-methoxy-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid;

7β-[[[(t-butylaminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid; and

7β-[[[(n-pentylaminocarbonyl)amino](D-2-thienyl)acetyl]amino]-7α-methoxy-3-[[(1-oxopyridazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylicacid respectively.

Similarly, by employing the methylisocyanate from example 81 or thealkylisocyanates of examples 82-88 in the procedure of examples 12 to 18other compounds within the scope of this invention are obtained.

EXAMPLES 89-106

Following the procedure of example 1 but employing the appropriate esterof 7-aminocephalosporanic acid or by reacting the final product ofexample 1, esters and salts of the following formula are obtained

    ______________________________________                                         ##STR68##                                                                    Ex.        R                                                                  ______________________________________                                        89         CH.sub.3                                                           90         t-C.sub.4 H.sub.9                                                  91                                                                                        ##STR69##                                                         92                                                                                        ##STR70##                                                         93                                                                                        ##STR71##                                                         94         Si(CH.sub.3).sub.3                                                 95         CH.sub.2CCl.sub.3                                                  96                                                                                        ##STR72##                                                         97                                                                                        ##STR73##                                                         98                                                                                        ##STR74##                                                         99                                                                                        ##STR75##                                                         100                                                                                       ##STR76##                                                         101        Ca/2                                                               102        Mg/2                                                               103        Na                                                                 104        Al/3                                                               105        [CH.sub.3 NH.sub.3 ].sup.⊕                                     106        [(C.sub.6 H.sub.5 CH.sub.2).sub.2 NH.sub.2 ].sup.⊕             ______________________________________                                    

Similarly, the compounds of examples 3-88 can also be obtained in thevarious ester and salt forms shown in examples 89-106.

What is claimed is:
 1. A compound of the formula: ##STR77## wherein R ishydrogen, lower alkyl, phenyl-lower alkyl, diphenyllower alkyl,tri(lower alkyl)silyl, trihaloethyl, aluminum, an alkali metal ion, analkaline earth metal ion, dibenzylamine, N,N-dibenzylethylenediamine,lower alkylamine, N-lower alkylpiperidines, or ##STR78## R₁ ismonosubstituted or unsubstituted heterocyclic wherein said substituentis Cl, Br, or lower alkyl of 1-4 carbons and said heterocyclic isattached by way of an available carbon atom and is selected from thegroup consisting of thienyl, furyl, and pyrryl; R₂ is hydrogen or loweralkyl; R₄ is hydrogen, halogen, lower alkyl of 1-4 carbons, or loweralkoxy of 1-4 carbons, R₅ is hydrogen or lower alkyl; and R₆ is loweralkyl, phenyl, or phenyl-lower alkyl.
 2. The compound of claim 1 whereinR is hydrogen, lower alkyl of 1-4 carbons, benzyl, phenethyl,diphenylmethyl, trimethylsilyl, 2,2,2-trichloroethyl, aluminum, analkali metal, an alkaline earth metal, dibenzylamine,N,N-dibenzylethylenediamine, lower alkylamine, N-lower alkylpiperidines,or ##STR79## R₁ is monosubstituted or unsubstituted heterocyclic whereinsaid substituent is Cl, Br, or lower alkyl of 1-4 carbons and saidheterocyclic is attached by way of an available carbon atom and isselected from the group consisting of thienyl, furyl, and pyrryl; R₂ ishydrogen or lower alkyl of 1-4 carbons; R₅ is hydrogen or lower alkyl of1-4 carbons; and R₆ is lower alkyl of 1-4 carbons, phenyl, benzyl,phenethyl.
 3. The compound of claim 2 wherein R₂ is hydrogen.
 4. Thecompound of claim 3 wherein R₄ is hydrogen.
 5. The compound of claim 4wherein R₁ is selected from the group consisting of 2-thienyl,3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, and 3-pyrryl.
 6. The compound ofclaim 5 wherein R₁ is 2-thienyl or 3-thienyl.
 7. The compound of claim 6wherein R₁ is 2-thienyl.
 8. The compound of claim 2 wherein R₂ is loweralkyl of 1-4 carbons.
 9. The compound of claim 8 wherein R₄ is hydrogen.10. The compound of claim 9 wherein R₁ is selected from the groupconsisting of 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyrryl, and3-pyrryl.
 11. The compound of claim 10 wherein R₁ is 2-thienyl or3-thienyl.
 12. The compound of claim 11 wherein R is hydrogen; R₁ is2-thienyl; and R₂ is methyl.